The normal fidelity of chromosome replication in untransformed cells is maintained by coordinately regulated cellular pathways that sense DNA alterations, modulate cell-cycle progression, and restore DNA integrity. Of these diverse cellular activities, the regulation of cell-cycle progression has the most profound effect on the chromosome stability of a cell exposed to adverse environmental conditions. Previous studies by us and other have demonstrated an increase in chromosome instability either by the deregulated expression of proto-oncogenes such as ras that accelerates cell proliferation or through the loss of negative growth regulators such as p53 and Rb that modulate a G1/S-phase transition. In addition to aberrant cell gene products, viral oncogene products such as the human papillomavirus E6 and E7 proteins are also able to increase genomic instability by reducing or eliminating a G1/S-phase checkpoint through inhibition of p53 and Rb, respectively. Oncogene overexpression is sufficient to rapidly (within a few cell divisions) enhance genomic instability. In contrast, abrogation of a cell-cycle checkpoint by the viral products E6 and E7 has a small effect on chromosome integrity in unperturbed cells. However, when E6 and E7 expressing cells are challenged by a growth restrictive stress or by exposure to DNA damaging agents, they become genomically unstable. Thus, the goals of this study are to use the human papillomavirus E6 and E7 genes as tools: 1) to investigate the differences and similarities between the modulation of wild-type p53 activity by hypoxia vs ionizing radiation, and 2) to explore the mechanism of genomic instability and apoptosis induced by hypoxia. The results obtained from this study will give us new insights into how tumor specific physiological stresses such as hypoxia modulate viral oncogene products that have been implicated in the initiation of cervical carcinoma. The above proposed studies are predicted on two distinct differences we have found between p53 induction by DNA damaging agents and p53 induction by hypoxia. First, although hypoxia causes the accumulation of nuclear p53 DNA binding and transcriptional enhancing activity, the G1/S-phase block found only in wild-type p53 cell lines after ionizing radiation is found after hypoxia in both wild type and mutant p53 cell lines. Secondly, cells expressing the E6 gene from human papillomavirus (HPV type 16 or 18) fail to accumulate p53 in response to ionizing radiation and fail to induce a G1/S-phase checkpoint due to increased degradation of p53 by ubiquitination. In contrast, E6 expressing cells do increase their p53 levels when exposed to hypoxia, and induce a G1/S-phase checkpoint. These results indicate that the signal transduction pathway for growth arrest induced by hypoxia is distinct from the signal transduction pathway for growth arrest induced by ionizing radiation. We also present data to indicate that the induction of apoptosis by hypoxia is dependent on wild- type p53 activity and propose that hypoxia selects for cervical carcinomas that have lost their ability to undergo apoptosis, leading to a tumor that responds poorly to radiation or chemotherapy.